Combined Chemoprevention Using a Nanotechnology-based Therapeutic System

描述（由申请人提供）： 结直肠癌（CRC）是美国癌症死亡的第二大常见原因，每年报告的死亡人数超过56，000人。虽然手术和化疗一直是主要的疾病干预方法，但化学预防已成为诊断和治疗的替代方法，因为化学预防剂预防CRC的能力的证据变得可用。在使用临床前和临床模型测试的药物中，阿司匹林、钙和叶酸受到了极大的关注。当单独使用时，所有这些药物都显示出减少CRC的效果。然而，一些研究报告了严重的副作用，特别是阿司匹林，包括胃肠道出血和与化学预防所需的高剂量相关的血小板功能障碍。联合治疗的兴趣一直在增加，因为其他有前途的化学预防剂已显示出协同效应，最小化毒性。联合治疗的研究仍处于起步阶段，因此需要在这一领域做出更多的努力。选择合适的药物递送系统对于确保药物到达其预期作用部位也很重要。使用靶向系统将化学预防剂的组合直接递送到局部结肠环境中将导致较低的剂量，具有较小的毒性作用机会，同时保持功效。使用这种载体系统的潜在好处是显而易见的，但其在化学预防中的应用从未被研究过，这表明需要在这一领域进行研究。因此，该初步研究的总体目标是开发使用独特的基于纳米技术的结肠靶向递送系统递送的化学预防剂的有效的新型组合以预防CRC。本申请的具体目的是：（1）设计和制备一种新的基于纳米技术的药物递送系统，该系统能够将阿司匹林、钙和叶酸的预定组合直接包封和递送到结肠中;（2）根据药物靶向结肠、与结肠壁的生物粘附和药物释放来评估所制备的纳米颗粒制剂;（3）使用动物模型评估阿司匹林、钙和叶酸的组合对CRC的协同化学预防作用，同时使毒副作用最小化。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second most common cause of cancer death in the United States with more than 56,000 deaths reported each year. While surgery and chemotherapy have been the major disease intervention methods, chemoprevention has emerged as an alternative to diagnosis and treatment, as evidence of the ability of chemopreventive agents to prevent CRC becomes available. Among agents being tested using preclinical and clinical models, aspirin, calcium and folic acid have received significant attention. All of these agents have shown effects in reducing CRC, when used individually. However, several studies have reported severe side effects, especially for aspirin, including gastrointestinal bleeding and platelet dysfunction associated with high doses needed for chemoprevention. The interest in combination therapy has been increasing, as other promising chemopreventive agents have shown synergistic efficacy with minimized toxicity. Research in combination therapy is still in its infancy; hence more efforts in this area are warranted. The selection of an appropriate drug delivery system is also of importance to ensure that drug reaches its intended site of action. Delivering combinations of chemopreventive agents using a targeted system directly into the local colonic environment would result in lower doses with lesser chances of toxic effects, while maintaining efficacy. The potential benefits of using such carrier systems is apparent, however its application in chemoprevention has never been studied, demonstrating a need for research in this area. Thus, the overall goal of this pilot study is to develop an effective novel combination of chemopreventive agents delivered using a unique nanotechnology- based colon-targeting delivery system to prevent CRC. The specific aims of our application are : (1) to design and prepare a novel nanotechnology-based drug delivery system capable of encapsulating and delivering predetermined combinations of aspirin, calcium and folic acid directly into the colon; (2) to evaluate the prepared nanoparticle formulations in terms of drug targeting to the colon, bioadhesion to the colonic wall and drug release; (3) to assess the synergistic chemopreventive effects of a combination of aspirin, calcium and folic acid against CRC while minimizing toxic side effects, using an animal model.